CN115160299A

CN115160299A - Xanthine oxidase inhibitor

Info

Publication number: CN115160299A
Application number: CN202210463461.7A
Authority: CN
Inventors: 史东方; 傅长金; 杨艳
Original assignee: Jiangsu Atom Bioscience and Pharmaceutical Co Ltd
Current assignee: Jiangsu Atom Bioscience and Pharmaceutical Co Ltd
Priority date: 2021-04-29
Filing date: 2022-04-28
Publication date: 2022-10-11
Also published as: CA3218011A1; WO2022233264A1; AU2022270242A1; TW202246238A; BR112023022484A2; KR20240005050A; JP2024516040A; EP4335844A1

Abstract

The invention relates to a xanthine oxidase inhibitor which is a compound shown as a general formula (I) or a pharmaceutically acceptable salt thereof and has excellent xanthine oxidaseThe enzyme has the potential application value in the aspects of anti-gout drugs, anti-hyperuricemia drugs and the like.

Description

Xanthine oxidase inhibitor

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a compound with an inhibitory effect on xanthine oxidase.

Background

Gout (gout) is a disease caused by hyperuricemia and/or unsmooth excretion of uric acid due to long-term purine metabolic disorder in human body, blood uric acid (sUA) level is continuously increased, sodium urate is crystallized and deposited in vivo. It is mainly manifested by recurrent joint redness, swelling, heat, pain and dysfunction, even joint deformity, nephrolithiasis and uric acid nephropathy.

In recent years, with the improvement of living standard, the dietary structure of people is changed, and the number of gout patients is increased remarkably. Gout has become the second largest metabolic disease after diabetes, and the disease has been listed as one of the 21 st century and twenty-old persistent ailments by the united nations. According to The data of The National Health and Nutrition Survey of The United states, the prevalence of Gout in The adult Population of The United states is 3.9% (approximately 830 million people) between 2007 and 2008 (Zhu Y, pandya BJ, choi HK.Presence of Gout and Hyperuricemia in The US General position: the National Health and Nutrition evaluation Survey 2007-2008J. Arthritis Rheum,2011,63 (10): 3136-3141); meta analysis shows that the overall prevalence of hyperuricemia in China is 13.3% and gout is 1.1% (Liu R, han C, wu D, et al.Presence of hyperuricemia and gout in mainland China from 2000to 2014. The incidence of gout has also increased over the past decades due to the prevalence of comorbid diseases that can contribute to hyperuricemia (e.g., hypertension, obesity, metabolic syndrome, type 2 diabetes, chronic kidney disease) (Khanna D, fitzgerald JD, khanna PP, et al, american College of rhematologic Guidelines for Management of go. Part 1 systematic nonapharmacogenic and pharmaceutical Therapeutic Approaches hyperuricemia [ j ]. Arthritis Care & Research,2012,64 (14410): 1432-1436).

Gout treatment comprises two aspects of drug treatment and non-drug treatment. Non-drug therapy is an important component of gout therapy, including diet control and lifestyle modification (e.g., weight loss, physical exercise). The medical treatment of chronic Gout is often focused on reducing sUA levels (Qaseem A, harris R, foricea MA. Clinical Guidelines Committee of the ACP. Management of Acute and Recurrent Gout: A Clinical Practice Guidelines from the American College of Physicians [ J ]. Annals of Internal Medicine,2017,166 (1): 58-68). The existing medicines for treating gout mainly comprise three main types: anti-acute gouty arthritis, uric acid excretion promoting agent, and uric acid production inhibiting agent.

The medicine for resisting acute gouty arthritis such as colchicine, non-steroidal anti-inflammatory drug (NSAIDS), adrenocorticotropic hormone, glucocorticoid and the like is mainly used for treating acute gouty arthritis and can relieve temporary pain of patients. Wherein colchicine is often accompanied with common adverse reactions such as diarrhea, emesis, abdominal pain spasm, etc. NSAIDS can relieve pain in a short period of time, but most NSAIDS are associated with severe gastrointestinal reactions. Corticotropin and glucocorticoid can inhibit noninfectious inflammation, relieve congestion and edema, inhibit inflammatory cell migration and reduce autoimmune level, and is used for treating patients with severe acute gout accompanied with systemic symptoms, but the medicines have strong rebound effect.

The uricosuric drugs mainly comprise probenecid, lesinurad, benzbromarone and the like. The medicine can inhibit reabsorption of uric acid by renal tubule, and act on urate transporter of renal proximal convoluted tubule to inhibit reabsorption of uric acid, increase excretion of uric acid, and reduce uric acid concentration in vivo. Probenecid is the first choice of a single-drug uricosuric drug in the U.S. guidelines, but is limited in application due to multiple significant interactions with some commonly used drugs (such as non-steroidal anti-inflammatory drugs, beta-lactams, heparin, etc.). Lesinurad is a novel urate transporter 1 (URAT 1) inhibitor approved by the FDA in 2015, whose drug specification warns in black boxes of the risk of (potentially lethal) acute renal failure and cardiovascular disease. For the above reasons, lesinurad is not recommended for patients with heart failure combined with uncontrolled hypertension, unstable angina, recent myocardial infarction, or NYHA grades III-IV in cardiac function. End stage renal disease, kidney transplantation or dialysis patient disablement (Bardin T, richette p. Novel urocerics [ J ]. Rheumatology,2018,57 (suppl. 1): i42-i 46). Benzbromarone is an effective uricosuric agent, has been approved for sale in many countries, but is not approved in the united states. Benzbromarone was withdrawn from europe in some countries in 2003 due to severe hepatotoxicity, but is still used to treat gout in some countries. Until now, benzbromarone has been considered as an effective drug for gout patients who are intolerant to allopurinol due to cyclosporin treatment after organ transplantation in japan, australia, new zealand and some european countries. As the liver-related adverse events related to benzbromarone have ethnicity difference, chinese hyperuricemia and gout diagnosis and treatment guidelines (2019) recommend benzbromarone as a first-line uric acid reducing medicine.

In human metabolism, xanthine oxidase catalyzes the last two steps in purine metabolism, oxidation of hypoxanthine to xanthine and oxidation of xanthine to uric acid, and the continuous rise of uric acid concentration in blood leads to the occurrence of various diseases including gout. Therefore, xanthine oxidase is closely related to gout, and by inhibiting xanthine oxidase, a pathway for purine to be metabolized into uric acid in a human body can be blocked, the level of sUA is effectively reduced, and the occurrence and development of gout and hyperuricemia can be prevented and treated. Compounds having xanthine oxidase inhibitory activity which have been publicly reported include a class of compounds having a structure represented by the following formula (G) disclosed in CN102574839A, and a class of compounds having a structure represented by the following formula (F) disclosed in patent CN103980267A which has been filed by the applicant earlier, and the like. The medicines on the market at present mainly comprise allopurinol and febuxostat.

Allopurinol is an analogue of hypoxanthine and is recommended as a first-line therapeutic agent for the treatment of chronic gout. But allopurinol is poorly therapeutic, and related studies indicate that subjects achieve a therapeutic endpoint rate of less than 50% even when allopurinol is used to the maximum Dose (Robert M, douglas CA, scott b. Less than half of the halo of wounds treated with high-Dose allopurinol reach serum uric acid target [ J ]. ACR/ARHP annular measuring, 2017, abstract number 1120. It also causes skin rashes and other rare but fatal side effects including Stevens-Johnson syndrome, toxic epidermal necrolysis with a mortality rate of about 10% to 30% (Bocquet H, bagot M, roujeau JC, drug-induced pseudomonas and drug hypersensitive syndrome (drug rat with eosinophia and system systems: DRESS [ J ]. Seninars in Current Medicine and Surgery,1996,15 (4): 250-257) other side effects of allopurinol including stomach discomfort, nausea, abdominal pain, diarrhea, leukopenia and thrombocytopenia, headache, fever, loss of appetite, weight loss, painful urination, pruritis, and lethargy.

Febuxostat is a new generation XOI, can inhibit the oxidation state and the reduction state of xanthine oxidase, but due to cardiovascular toxicity (such as the risk of sudden death), the U.S. food and drug administration requires black box risk warning on the drug specification, and adjusts prescription information in 2019 to change from first-line medication to second-line medication. The new england medical journal in 3 months in 2018 published a study result publication of 6190 gout patients: the investigators found that the risk of adverse cardiovascular events was similar for the febuxostat and allopurinol treated groups as a whole after 32 months of average treatment (HR 1.03, 95% ci, 0.87-1.23), but the all-cause mortality and cardiovascular mortality was higher for the febuxostat group than for the allopurinol group. The cardiovascular mortality of patients in the febuxostat group increased by 34% (HR 1.34, 95% CI, 1.03-1.73), the all-cause mortality by 22% (HR 1.22, 95% CI, 1.01-1.47). Sudden cardiac death is most common among The causes of cardiovascular death, with 83 cases (2.7%) in The febuxostat group and 56 cases (1.8%) in The allopurinol group (William B, kenneth G, michael A, et al, cardiovascular safety of febuxostat or allopurinol in tissues with gout [ J ]. The New England Journal of Medicine,2018, 378. In addition, febuxostat may also cause severe gastrointestinal toxic and side effects, renal toxic and side effects, liver dysfunction, and the like.

So far, xanthine oxidase inhibitors, including allopurinol and febuxostat, have a great risk of sudden death and serious toxicity problems in the kidney, liver, gastrointestinal tract and the like, so that the use of such drugs is greatly limited, and the development of drugs of xanthine oxidase target inhibitors is relatively few.

Disclosure of Invention

The present invention aims to provide a compound having xanthine oxidase inhibitory activity, based on the prior art.

Another object of the present invention is to provide the preparation of the above-mentioned compounds and their use in the medical field.

The technical scheme of the invention is as follows:

a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

y is N or C-R ⁶ ；

R ¹ Is cyano, nitro or halogen;

R ² 、R ³ or R ⁴ Each independently is hydrogen, deuterium, cyano, halogen, hydroxy, amino, nitro, C _1-6 Alkyl, substituted C _1-6 Alkyl radical, C _1-6 Alkoxy or substituted C _1-6 An alkoxy group; wherein R is ² 、R ³ Or R ⁴ The substituents in each related group are independently selected from deuterium, hydroxyl, cyano, halogen and C _1-4 Alkyl or C _1-4 One or more of alkoxy groups;

R ⁵ is C _1-6 Alkyl, substituted C _1-6 Alkyl radical, C _3-6 Cycloalkyl, substituted C _3-6 Cycloalkyl radical, C _3-6 Heterocycloalkyl or substituted C _3-6 A heterocycloalkyl group; wherein R is ⁵ The substituent in each group is selected from deuterium, cyano, nitro, halogen and C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl or C _3-6 One or more of heterocycloalkyl;

R ⁶ is hydrogen, deuterium, halogen, cyano, C _1-6 Alkyl, substituted C _1-6 Alkyl radical, C _1-6 Alkoxy, substituted C _1-6 Alkoxy radical, C _3-6 Cycloalkyl or substituted C _3-6 A cycloalkyl group; wherein R is ⁶ The substituent in each group is selected from deuterium, cyano, nitro, halogen and C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Alkylthio or C _3-6 One or more of cycloalkyl;

ar is the following unsubstituted or substituted group: 1,2, 3-triazolyl, pyrazolyl, pyridyl or thienyl, wherein the substituents in each group referred to by Ar are selected from deuterium, halogen or C _1-3 One or more of alkyl; and when Y is C-R ⁶ When Ar is only an unsubstituted or substituted 1,2, 3-triazolyl group;

R ⁷ is carboxyl or C _2-6 An ester group.

In a preferred embodiment, ar is a substituted or unsubstituted group selected from the group consisting of:

in a preferred embodiment, ar is a substituted or unsubstituted group as follows, and "-" is the site of attachment of Ar to the phenyl ring:

in a preferred embodiment, ar isThe substituents in each group concerned are selected from deuterium, halogen or C _1-3 One or more of alkyl groups.

In a preferred embodiment, R ² 、R ³ Or R ⁴ Each independently hydrogen, deuterium, cyano or halogen.

In a preferred embodiment, R ⁵ Is C _3-6 Alkyl, substituted C _1-6 Alkyl radical, C _3-6 Cycloalkyl, substituted C _3-6 Cycloalkyl radical, C _3-6 Heterocycloalkyl or substituted C _3-6 A heterocycloalkyl group; wherein R is ⁵ The substituent in each group is selected from deuterium, cyano, nitro, halogen and C _1-5 Alkyl radical, C _1-5 Alkoxy or C _3-6 One or more cycloalkyl groups.

In a preferred embodiment, R ⁵ Is C _3-6 Alkyl, substituted C _1-6 Alkyl radical, C _3-6 Cycloalkyl, substituted C _3-6 Cycloalkyl, tetrahydrofuran, substituted tetrahydrofuran, tetrahydrothiophene, substituted tetrahydrothiophene, tetrahydropyrrole, or substituted tetrahydropyrrole; wherein R is ⁵ The substituent in each group is selected from deuterium, cyano, nitro, halogen and C _1-5 Alkyl radical, C _1-5 Alkoxy or C _3-6 One or more cycloalkyl groups.

In a more preferred embodiment, R ⁵ Is isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, tetrahydrofuran, tetrahydrothiophene or tetrahydropyrrole.

In a preferred embodiment, R ⁶ Is hydrogen, deuterium, halogen, cyano or C _1-5 An alkyl group.

In a preferred embodiment, the compounds of the invention may be selected from:

the invention also comprises a pharmaceutical composition which takes the compound or the pharmaceutically acceptable salt thereof as an active substance and is assisted by pharmaceutically acceptable auxiliary materials.

The compound or the pharmaceutically acceptable salt thereof can be applied to the preparation of xanthine oxidase inhibitor medicines, in particular to the preparation of anti-gout medicines or anti-hyperuricemia medicines.

The radicals indicated in the present invention have the following meanings, unless explicitly defined otherwise:

"H", i.e., hydrogen, refers to protium (1H), which is the predominant stable isotope of hydrogen.

"D", or "deuterium", refers to a stable form isotope of hydrogen, also known as deuterium, and the element symbol is D.

"halogen" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

"hydroxy" refers to an-OH group.

"amino" refers to the group-NH ₂ A group.

"alkyl" means a saturated aliphatic radical containing from 1 to 10 carbon atoms, including straight and branched chain radicals (a numerical range referred to herein, e.g., "1 to 10", means that the radical, in this case alkyl, may contain from 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms). Alkyl groups containing 1 to 4 carbon atoms are referred to as lower alkyl groups. When a lower alkyl group has no substituent, it is referred to as unsubstituted lower alkyl. The alkyl group may be selected from C _1-6 Alkyl radical, C _1-5 Alkyl radical, C _1-4 Alkyl radical, C _1-3 Alkyl radical, C _1-2 Alkyl radical, C _2-3 Alkyl radical, C _2-4 Alkyl groups, and the like. Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, and the like. Alkyl groups may be substituted or unsubstituted.

"cycloalkyl" means a saturated cyclic aliphatic group containing from 3 to 10 carbon atoms, and reference to a numerical range in this application, such as "3 to 10", means that the group, which is then cycloalkyl, may contain 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and the like, up to and including 10 carbon atoms as ring atoms. Cycloalkyl can be selected from C _3-8 Cycloalkyl radical, C _3-6 Cycloalkyl radical, C _3-5 CycloalkanesBase, C _3-4 Cycloalkyl radical, C _3-9 Cycloalkyl radical, C _4-6 Cycloalkyl groups, and the like. Specific alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Cycloalkyl groups may be substituted or unsubstituted.

"Heterocycloalkyl" means a saturated cyclic group containing from 3 to 10 ring atoms containing one or more heteroatoms selected from N, O, S. Reference herein to a numerical range, such as "3 to 6", means that the group, which is then heterocycloalkyl, may contain 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 6 carbon atoms as ring atoms. The heterocycloalkyl group may be C _3-8 Heterocycloalkyl radical, C _3-6 Heterocycloalkyl radical, C _3-5 Heterocycloalkyl radical, C _3-4 Heterocycloalkyl radical, C _3-9 Heterocycloalkyl radical, C _4-6 Heterocycloalkyl, and the like. Specific alkyl groups include, but are not limited to, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, 1, 4-dioxane, oxospiro [3,3 ]]Heptylalkyl, oxospiro [4,4 ]]Nonanyl, oxo spiro [5,5]Undecyl, oxospiro [6,6 ]]Tridecyl, oxobicyclo [1,1]Pentyl alkyl, oxo-bicyclo [2,2,2]Octyl, oxobicyclo [3,2,1 ]]Octyl and azaspiro [3,3 ]]Heptaalkyl, azaspiro [4,4]Nonanyl, azaspiro [5,5]Undecyl, azaspiro [6,6]Tridecyl, azabicyclo [1,1 ] s]Pentyl alkyl, azabicyclo [2,2 ]]Octyl or azabicyclo [3,2,1 ] groups]An octyl group and the like. Heterocycloalkyl groups may be substituted or unsubstituted.

"haloalkyl" refers to an alkyl group wherein one, two, three, four or more hydrogens of the alkyl group are replaced with one or more halogens; wherein the alkyl group may be C _1-6 Alkyl radical, C _1-5 Alkyl radical, C _1-4 Alkyl radical, C _1-3 Alkyl radical, C _1-2 Alkyl radical, C _2-3 Alkyl radical, C _2-4 Alkyl groups, and the like. It includes, but is not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethyl, dichloromethyl, trichloromethyl, monobromomethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, and the like.

"alkoxy" denotes the-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl) groups, which are substituted by one or more halogen atomsFurther represents-O- (unsubstituted alkyl). Wherein the alkyl group may be C _1-6 Alkyl radical, C _1-5 Alkyl radical, C _1-4 Alkyl radical, C _1-3 Alkyl radical, C _1-2 Alkyl radical, C _2-3 Alkyl radical, C _2-4 Alkyl groups, and the like. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, cyclopropoxy, and the like.

"alkylthio" means the groups-S- (unsubstituted alkyl) and-S- (unsubstituted cycloalkyl), which further means-S- (unsubstituted alkyl). Wherein the alkyl group may be C _1-6 Alkyl radical, C _1-5 Alkyl radical, C _1-4 Alkyl radical, C _1-3 Alkyl radical, C _1-2 Alkyl radical, C _2-3 Alkyl radical, C _2-4 Alkyl groups, and the like. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, cyclopropylthio and the like.

"cyano," refers to the group-CN.

"nitro" means-NO ₂ A group.

"carboxyl" refers to the-COOH group.

"1,2, 3-triazolyl" means

Any one of them.

"pyrazole" means

Any one of them.

"thiophene" means

Any one of them.

"ester group" means a "-C (= O) -O-alkyl" group, wherein the alkyl group may be selected from C _1-6 Alkyl radical, C _1-5 Alkyl radical, C _1-4 Alkyl radical, C _1-3 Alkyl radical, C _1-2 Alkyl radical, C _2-3 Alkyl radical, C _2-4 Alkyl groups, and the like. Representative examples include, but are not limited to, methyl formate, ethyl formate, n-propyl formate, isopropyl formate, and the like.The substituted ester group means that hydrogen in the ester group is substituted by one substituent, or a plurality of hydrogens in the ester group are respectively substituted by the same or different substituents.

"pharmaceutically acceptable salts" are salts comprising a compound of formula (I) with an organic or inorganic acid, and refer to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include, but are not limited to:

(1) Salts with acids are formed by reaction of the free base of the parent compound with inorganic acids such as, but not limited to, hydrochloric, hydrobromic, nitric, phosphoric, metaphosphoric, sulfuric, sulfurous, and perchloric acids or organic acids such as, but not limited to, acetic, propionic, acrylic, oxalic, (D) or (L) malic, fumaric, maleic, hydroxybenzoic, γ -hydroxybutyric, methoxybenzoic, phthalic, methanesulfonic, ethanesulfonic, naphthalene-1-sulfonic, naphthalene-2-sulfonic, p-toluenesulfonic, salicylic, tartaric, citric, lactic, mandelic, succinic, or malonic acids, and the like.

(2) The acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or a salt formed by complexing with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine or the like.

"pharmaceutical composition" refers to a mixture of one or more compounds described herein or their pharmaceutically acceptable salts and prodrugs with other chemical ingredients, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

The invention further claims a pharmaceutical composition comprising any of the compounds described above, pharmaceutically acceptable salts thereof, or easily hydrolysable prodrugs thereof, and other pharmaceutically active ingredients.

The invention also includes any compound and pharmaceutically acceptable salt thereof, which can be prepared into any clinically or pharmaceutically acceptable dosage form by the method known in the art. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; can also be made into oral liquid preparation, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine.

The compounds provided by the invention have excellent xanthine oxidase inhibitory activity, can also significantly reduce the serum uric acid level of a rat model with hyperuricemia, and have potential application values in the aspects of anti-gout drugs, anti-hyperuricemia drugs and the like. Because febuxostat has serious sudden cardiac death, serious renal toxicity and liver toxicity, the compound provided by the invention has certain advantages in the aspect of reducing drug toxicity, and has good drug development prospect.

Detailed Description

The detection method of the present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.

Example 1: synthesis of 2- (3-cyano-1-isopropyl-1H-indol-5-yl) -5-methyl-2H-1, 2, 3-triazole-4-carboxylic acid (7)

Step A: a solution of sodium nitrite (3.13g, 45.4mmol) in water (20 mL) was added dropwise to a mixture containing 5-aminoindole (5.0g, 37.8mmol), water (80 mL) and 6M hydrochloric acid (18.9 mL) in an ice-water bath. After the addition was complete, stirring was continued at this temperature for 30 minutes. Ethylacetoacetate (10.8g, 83.2mmol) was added dropwise, and a solution of sodium acetate (93.1g, 1.13mol) in water (100 mL) was added dropwise to adjust the pH to neutral. After the addition was complete, stirring was continued at this temperature for 30 minutes. The mixture was filtered, the filtrate was extracted with dichloromethane (300 mL. Times.3), and the combined organic phases were washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1: 10-2, elution) to give ethyl 2- [2- (1H-indol-5-yl) hydrazino ] -3-oxobutanoate (1) (1.77 g). The yield thereof was found to be 14.3%.

And B: a mixture containing Compound 1 (1.50g, 5.49mmol), ammonium acetate (4.23g, 54.9mmol), copper chloride (1.62g, 12.1mmol) and ethanol (20 mL) was stirred at reflux overnight. Cooled to room temperature and the pH value is adjusted to 1-2 with 1M hydrochloric acid. Filtration and purification of the filter cake by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1: 10-1, elution) gave ethyl 2- (1H-indol-5-yl) -5-methyl-2H-1, 2, 3-triazole-4-carboxylate (2) (700 mg). The yield thereof was found to be 47.2%.

Step C: DMF (30.5mg, 0.418mmol) was added dropwise to a solution of oxalyl chloride (53.00mg, 0.418mmol) in dichloromethane (3 mL) in an ice-water bath. After the addition was complete, the mixture was stirred at this temperature for a further 0.5 h. Compound 2 (100mg, 0.370mmol) was further added, and the resulting mixture was stirred under reflux for 1 hour. THF (8 mL) and a solution of amine acetate (1.80g, 23.4 mmol) in water (8 mL) were added. The temperature was raised to 80 ℃ and stirring was continued for 0.5 hour. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL. Times.2), and the combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give a crude product (100 mg) of ethyl 2- (3-formyl-1H-indol-5-yl) -5-methyl-1, 2, 3-triazole-4-carboxylate (3). This compound was used in the next reaction without purification. MS (ESI, m/z): 299.2[ 2 ] M + H] ⁺ 。

Step D: a mixture containing crude compound 3 (100 mg), hydroxylamine hydrochloride (26.5mg, 0.381mmol) and pyridine (3 mL) was stirred at reflux for 1 hour. After cooling to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL. Times.2), and the combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1]-1H-indol-5-yl } -5-methyl-2H-1, 2, 3-triazole-4-carboxylic acid ethyl ester (4) (80 mg). The total yield of the two reactions of the step C and the step D is 76.4 percent. MS (ESI, m/z): 314.2[ M ] +H] ⁺ 。

Step E: a mixture containing compound 4 (80mg, 0.255mmol), THF (1 mL), and thiocarbonyldiimidazole (132mg, 0.740 mmol) was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1: 10-1, elution) to give ethyl 2- (3-cyano-1H-indol-5-yl) -5-methyl-2H-1, 2, 3-triazole-4-carboxylate (5) (75 mg). The yield thereof was found to be 99.6%. ¹ H NMR(DMSO-d ₆ ，400MHz)δ12.52(s，1H)，8.40(d，J＝2.4Hz，1H)，8.19(d，J＝1.6Hz，1H)，8.00-7.97(m，1H)，7.74(d，J＝9.2Hz，1H)，4.39(q，J＝6.8Hz，2H)，2.56(s，3H)，1.36(t，J＝6.8Hz，3H)。

Step F: a mixture containing Compound 5 (75mg, 0.254mmol), isopropyl iodide (95mg, 0.559mmol), cesium carbonate (166mg, 0.508mmol) and acetonitrile (3 mL) was stirred at 80 ℃ overnight. Cooling to room temperature. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (10 mL. Times.3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, 15-1, elution) to give ethyl 2- (3-cyano-1-isopropyl-1H-indol-5-yl) -5-methyl-2H-1, 2, 3-triazole-4-carboxylate (6) (70 mg). The yield thereof was found to be 81.7%.

G: a mixture containing compound 6 (60mg, 0.178mmol), hydrated lithium hydroxide (30mg, 0.715mmol), water (0.8 mL) and THF (3.2 mL) was stirred at room temperature overnight. The pH value is adjusted to 3-4 by 1M hydrochloric acid. The solvent was evaporated under reduced pressure and then purified by preparative HPLC to give 2- (3-cyano-1-isopropyl-1H-indol-5-yl) -5-methyl-2H-1, 2, 3-triazole-4-carboxylic acid (7). ¹ H NMR(DMSO-d ₆ ，400MHz)δ8.60(s，1H)，8.18(d，J＝2.0Hz，1H)，8.02-7.94(m，2H)，4.95-4.89(m，1H)，2.55(s，3H)，1.51(d，J＝6.8Hz，6H)。MS(ESI，m/z)：310.2[M+H] ⁺ 。

Example 2: synthesis of ethyl 2- (3-cyano-1-isopropyl-1H-indol-5-yl) -2H-1,2, 3-triazole-4-carboxylate (14)

Step A: a mixture containing 5-nitro-1H-indole (30.0 g, 185mmol), isopropyl iodide (69.2g, 407mmol), cesium carbonate (121g, 370mmol) and acetonitrile (500 mL) was stirred at 80 ℃ overnight. Cool to room temperature, filter, and rinse the filter cake with ethyl acetate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, 50-1. The yield thereof was found to be 100%.

And B: to a solution of compound 8 (38.0 g, 185mmol) in THF (50 mL) and methanol (200 mL) was added 10% palladium on carbon (4.0 g), and after the addition was complete, the resulting mixture was stirred under hydrogen at room temperature for 60 hours. Filter through celite and the filter cake is rinsed with ethyl acetate. The solvent was distilled off under reduced pressure to give 5-amino-1-isopropyl-1H-indole (9) (30.0 g). The yield thereof was found to be 93.1%.

And C: a solution of sodium nitrite (4.40g, 63.8mmol) in water (30 mL) was added dropwise to a mixture containing compound 9 (10g, 57.4mmol), water (200 mL) and 3M hydrochloric acid (54 mL) in an ice-water bath, and after completion of the addition, stirring was continued at that temperature for 1 hour. Then, the mixture was dropped into a mixture containing ethyl 3- (N, N-dimethylamino) acrylate (15.2g, 106mmol), sodium acetate (78.5g, 957 mmol) and water (500 mL) in an ice-water bath. After the addition was complete, stirring was continued at this temperature for 30 minutes. The mixture was extracted with methylene chloride (300 mL. Times.3), and the combined organic phases were washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, elution) to give ethyl 2- [2- (1-isopropyl-1H-indol-5-yl) hydrazino ] -3-oxopropanoate (10) (1.50 g). The yield thereof was found to be 8.67%.

Step D: a mixture containing compound 10 (1.50g, 4.98mmol), ammonium acetate (2.60g, 33.7 mmol), copper chloride (1.26g, 7.42mmol) and ethanol (18 mL) was stirred at reflux overnight. Cooled to room temperature and water (80 mL) was added. The mixture was extracted with ethyl acetate (40 mL. Times.2), and the combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, 7 elution) to give 2- (1-isopropyl-1H-indol-5-yl) -2H-1,2, 3-triazole-4-carboxylic acid ethyl ester (11) (310 mg). The yield thereof was found to be 20.9%. ¹ H NMR(CDCl ₃ ，400MHz)δ8.38(d，J＝2.0Hz，1H)，8.23(s，1H)，8.00(dd，J＝2.0，8.4Hz，1H)，7.44(d，J＝8.8Hz，1H)，7.31(d，J＝3.2Hz，1H)，6.61(d，J＝3.2Hz，1H)，4.75-4.68(m，1H)，4.48(q，J＝7.2Hz，2H)，1.56(d，J＝6.8Hz，6H)，1.45(t，J＝7.2Hz，3H)。MS(ESI，m/z)：299.1[M+H] ⁺ 。

See steps E, F and G for experimental procedures in turn C, D and E in example 1 to give ethyl 2- (3-cyano-1-isopropyl-1H-indol-5-yl) -2H-1,2, 3-triazole-4-carboxylate (14). ¹ H NMR(DMSO-d ₆ ，400MHz)δ8.64(s，1H)，8.61(s，1H)，8.24(d，J＝2.0Hz，1H)，8.08-7.98(m，2H)，4.98-4.89(m，1H)，8.40(q，J＝7.2Hz，2H)，1.51(d，J＝6.4Hz，6H)，1.36(t，J＝7.2Hz，3H)。MS(ESI，m/z)：324.2[M+H] ⁺ 。

Example 3: synthesis of 2- (3-cyano-1-isopropyl-1H-indol-5-yl) -2H-1,2, 3-triazole-4-carboxylic acid (15)

Experimental procedures for the synthesis of compound 15 starting from compound 14 are described in example 1, step G. ¹ H NMR(DMSO-d ₆ ，400MHz)δ8.62(s，1H)，8.52(s，1H)，8.23(s，1H)，8.07-7.97(m，2H)，4.95-4.92(m，1H)，1.51(d，J＝5.6Hz，6H)。MS(ESI，m/z)：296.1[M+H] ⁺ 。

Example 4: synthesis of 2- (3-cyano-1-isopropyl-1H-indazol-5-yl) -2H-1,2, 3-triazole-4-carboxylic acid (24)

Step A: a solution of sodium nitrite (4.35g, 63.1mmol) in water (50 mL) was added dropwise to 5-amino-1H-indazole (7.0 g,52.6 mmol) in 3M hydrochloric acid (53 mL) in an ice-water bath. After the addition was complete, stirring was continued at this temperature for 0.5 h. Then, the mixture was dropped into a mixture containing ethyl 3- (N, N-dimethylamino) acrylate (15.1g, 105mmol), sodium acetate (77.6g, 946mmol), ethanol (40 mL) and water (400 mL) in an ice-water bath. After the addition was complete, the resulting mixture was stirred at room temperature for 2 hours. Filtration and washing of the filter cake with water gave crude 2- [2- (1H-indazol-5-yl) hydrazino ] -3-oxopropanoic acid ethyl ester (16) (20.0 g). This compound was used in the next reaction without purification.

And B, step B: hydroxylamine hydrochloride (8.01g, 115mmol) and sodium acetate (18.9g, 231mmol) were added to a mixture containing the crude compound 16 (20.0 g), ethanol (100 mL) and water (50 mL). After the addition was complete, the resulting mixture was stirred at room temperature for 3 hours. Water (500 mL) was added, and the mixture was extracted with methylene chloride (200 mL. Times.2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give crude 2- [2- (1H-indazol-5-yl) hydrazino ] -3- (hydroxyimino) propionic acid ethyl ester (17) (14.5 g). This compound was used in the next reaction without purification.

And C: a mixture containing crude compound 17 (14.5 g), acetic acid (100 mL) and acetic anhydride (100 mL) was stirred at 60 ℃ for 4 hours. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1: 30-1, elution: 7) to give ethyl 2- (1-acetyl-1H-indazol-5-yl) -2H-1,2, 3-triazole-4-carboxylate (18) (1.80 g). The total yield of the three reactions of the steps A, B and C is 11.4%. ¹ H NMR(CDCl ₃ ，400MHz)δ8.59-8.56(m，1H)，8.52(d，J＝1.6Hz，1H)，8.42-8.39(m，1H)，8.26(s，1H)，8.22(s，1H)，4.49(q，J＝7.2Hz，2H)，2.82(s，3H)，1.46(t，J＝7.2Hz，3H)。MS(ESI，m/z)：300.2[M+H] ⁺ 。

Step D: a mixture containing compound 18 (1.80g, 6.01mmol), methanol (20 mL) and sodium hydroxide (962mg, 24.1mmol) was stirred at room temperature overnight. The pH value is adjusted to 1-2 by 1M hydrochloric acid. Filtration, rinsing of the filter cake with water and drying gave 2- (1H-indazol-5-yl) -2H-1,2, 3-triazole-4-carboxylic acid (19) (1.30 g). The yield thereof was found to be 94.3%.

Step E: thionyl chloride (3.37g, 28.4 mmol) was added dropwise to a solution of compound 19 (1.30g, 5.67mmol) in methanol (20 mL) under an ice-water bath, and after the addition was complete, the resulting mixture was stirred under reflux overnight. The solvent was distilled off under reduced pressure, followed by slurrying with methylene chloride to give methyl 2- (1H-indazol-5-yl) -2H-1,2, 3-triazole-4-carboxylate (20) (1.30 g). The yield thereof was found to be 94.2%.

Step F: potassium carbonate (2.73g, 19.7 mmol) and iodine (2.50g, 9.87mmol) were added to a solution of compound 20 (1.2g, 4.93mmol) in DMF (6 mL) in an ice-water bath, and after the addition was complete, the resulting mixture was stirred at room temperature overnight. Water (50 mL) was added and excess iodine was quenched with sodium thiosulfate solution. The mixture was extracted with ethyl acetate (50 mL. Times.2), and the combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give methyl 2- (3-iodo-1H-indazol-5-yl) -2H-1,2, 3-triazole-4-carboxylate (21) (790 mg). The yield thereof was found to be 43.4%. MS (ESI, m/z): 370.0 2[ M ] +H] ⁺ 。

Step G: a mixture containing compound 21 (780mg, 2.11mmol), DMF (10 mL), zinc cyanide (520mg, 4.43mmol) and tetrakis (triphenylphosphine) palladium (244mg, 0.211mmol) was stirred under nitrogen at 120 ℃ overnight. Insoluble matter was removed by filtration. Ethyl acetate (90 mL) was added, and the mixture was washed with saturated brine (50 mL. Times.3) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give methyl 2- (3-cyano-1H-indazol-5-yl) -2H-1,2, 3-triazole-4-carboxylate (22) (400 mg). The yield thereof was found to be 70.7%. MS (ESI, m/z): 269.1[ 2 ] M + H] ⁺ 。

Steps H and I Experimental procedure see Steps F and G of example 1 to give 2- (3-cyano-1-isopropyl-1H-indazol-5-yl) -2H-1,2, 3-triazole-4-carboxylic acid (24). ¹ H NMR(DMSO-d ₆ ，400MHz)δ13.74(s，1H)，8.58(s，1H)，8.42(s，1H)，8.31-8.23(m，2H)，5.32-5.22(m，1H)，1.55(d，J＝6.4Hz，6H)。MS(ESI，m/z)：296.9[M+H] ⁺ 。

Example 5: synthesis of 2- (3-cyano-1-isopropyl-1H-indazol-5-yl) thiophene-2-carboxylic acid (28)

Step A: a mixture containing 5-bromo-1H-indazole-3-carbonitrile (3.0g, 13.5 mmol), iodoisopropane (9.19g, 54.1mmol), cesium carbonate (8.80g, 27.0mmol) and DMF (50 mL) was stirred at 80 deg.CFor 1.5 hours. Cooled to room temperature and filtered to remove insoluble matter. Water (200 mL) was added, extraction was performed with ethyl acetate (80 mL. Times.3), and the combined organic phases were washed successively with water (50 mL. Times.2) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, 50-1, elution) to give 5-bromo-1-isopropyl-1H-indazole-3-carbonitrile (25) (2.10 g) and 5-bromo-2-isopropyl-2H-indazole-3-carbonitrile (26) (230 mg). The yields were 58.9% and 6.45%, respectively. Compound 25: ¹ H NMR(CDCl ₃ 400 MHz) δ 7.95 (d, J =1.2hz, 1h), 7.55 (dd, J =1.2,8.8hz, 1h), 7.45 (d, J =8.8hz, 1h), 4.93-4.87 (m, 1H), 1.61 (d, J =6.4hz, 6H). Compound 26: ¹ H NMR(CDCl ₃ ，400MHz)δ7.92(d，J＝1.2Hz，1H)，7.72(d，J＝8.8Hz，1H)，7.46-7.44(m，1H)，5.12-5.05(m，1H)，1.70(d，J＝6.4Hz，6H)。

and B: a mixture containing palladium acetate (16.6 mg, 0.0735mmol), 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (S-Phos) (60.3 mg, 0.147mmol) and THF (2 mL) was stirred under nitrogen for 30 minutes, then a solution of compound 25 (200mg, 0.735mmol), methyl 2-thiophenecarboxylate-5-boronic acid (150mg, 0.808mmol) and potassium carbonate (508mg, 3.67mmol) in water (1 mL) was added. After the addition was complete, the resulting mixture was stirred at 45 ℃ overnight. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL. Times.2), and the combined organic phases were washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, elution: 10) to give methyl 2- (3-cyano-1-isopropyl-1H-indazol-5-yl) -thiophene-2-carboxylate (27) (160 mg). The yield thereof was found to be 66.9%.

Step C for experimental procedure see step G in example 1 to give 2- (3-cyano-1-isopropyl-1H-indazol-5-yl) -thiophene-2-carboxylic acid (28). ¹ H NMR(DMSO-d ₆ ，400MHz)δ8.23(s，1H)，8.07(d，J＝8.8Hz，1H)，7.96-7.93(m，1H)，7.75(s，2H)，5.27-5.17(m，1H)，1.53(d，J＝6.4Hz，6H)。MS(ESI，m/z)：312.2[M+H] ⁺ 。

Example 6: synthesis of 1- (3-cyano-1-isobutyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylic acid (32)

Step A: a mixture containing ethyl 1H-pyrazole-4-carboxylate (3.79g, 27.0mmol), 5-bromo-1H-indazole-3-carbonitrile (3.0g, 13.5mmol), potassium carbonate (3.73g, 27.0mmol), cuprous iodide (2.57g, 13.5mmol), N' -dimethylethylenediamine (1.19g, 13.5mmol), and DMF (30 mL) was stirred at 110 ℃ under nitrogen overnight. After cooling to room temperature, ethyl acetate (300 mL) was added, the mixture was filtered, and the filtrate was washed with saturated brine (300 mL. Times.2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by preparative HPLC to give ethyl 1- (3-cyano-1H-indazol-5-yl) -1H-pyrazole-4-carboxylate (29) (600 mg). The yield thereof was found to be 15.8%.

And B: a mixture containing compound 29 (300mg, 1.07mmol), isopropyl iodide (328mg, 1.78mmol), cesium carbonate (581mg, 1.78mmol) and acetonitrile (3 mL) was stirred at 70 ℃ for 3 hours. Cooled to room temperature and filtered to remove insoluble matter. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL. Times.3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, 35-1, elution) to give 1- (3-cyano-1-isobutyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylic acid ethyl ester (30) (182 mg). The yield thereof was found to be 50.4%.

And C: a mixture containing compound 30 (100mg, 0.296mmol), lithium hydroxide hydrate (49.8mg, 1.19mmol), water (0.6 mL) and THF (3.4 mL) was stirred at 40 ℃ overnight. The solvent was evaporated under reduced pressure, water (20 mL) was added and the pH was adjusted to 1-2 with 1M hydrochloric acid. Extracted with ethyl acetate (30 mL. Times.2) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give a crude product (129 mg) of 1- (3-carbamoyl-1-isobutyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylic acid (31). This compound was used in the next reaction without purification.

Step D: to a solution of the crude compound 31 (120 mg) in dichloromethane (2 mL) were added trifluoroacetic anhydride (792mg, 3.77mmol) and pyridine (1.03g, 13.0 mmol), and after the addition was complete, the resulting mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added and the mixture was washed with 1M hydrochloric acid (50 mL. Times.2)Washed and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by preparative HPLC to give 1- (3-cyano-1-isobutyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylic acid (32). ¹ H NMR(DMSO-d ₆ ，400MHz)δ12.67(s，1H)，9.23(s，1H)，8.44(s，1H)，8.22-8.13(m，3H)，4.43(d，J＝7.2Hz，2H)，2.30-2.23(m，1H)，0.88(d，J＝6.4Hz，6H)。MS(ESI，m/z)：310.3[M+H] ⁺ 。

Example 7: synthesis of 1- (3-cyano-1-propyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylic acid (35)

See steps B, C and D in example 6 for experimental work in the synthesis of compound 35, where iodoisobutane in step B of example 6 was replaced with 1-bromopropane. ¹ H NMR(DMSO-d ₆ ，400MHz)δ9.22(s，1H)，8.43(d，J＝1.6Hz，1H)，8.22-8.13(m，3H)，4.56(t，J＝6.8Hz，2H)，1.95-1.88(m，2H)，0.85(t，J＝7.2Hz，3H)。MS(ESI，m/z)：296.3[M+H] ⁺ 。

Example 8: synthesis of 1- (3-cyano-1-isopropyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylic acid (38)

Experimental work for the synthesis of compound 38 is seen in steps B, C and D of example 6, where iodoisobutane in step B of example 6 is replaced with bromoisopropane. ¹ H NMR(DMSO-d ₆ ，400MHz)δ9.10(s，1H)，8.39(d，J＝1.6Hz，1H)，8.21-8.12(m，2H)，8.05(s，1H)，5.27-5.20(m，1H)，1.53(d，J＝6.4Hz，6H)。MS(ESI，m/z)：296.2[M+H] ⁺ 。

Example 9: synthesis of 2- (3-cyano-1-cyclopropylmethyl-1H-indol-5-yl) -2H-1,2, 3-triazole-4-carboxylic acid (41)

Step A: a mixture containing 5-bromo-1H-indole-3-carbonitrile (1.0 g, 4.52mmol), cyclopropylbromomethane (1.83g, 13.57mmol), cesium carbonate (4.42g, 13.57mmol) and acetonitrile (10 mL) was stirred at 80 ℃ for 4 hours. Cool to room temperature, filter, and rinse the filter cake with ethyl acetate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1. The yield thereof was found to be 94.9%.

And B, step B: to a solution of compound 39 (940mg, 3.42mmol) and methyl 1,2, 3-triazole-4-carboxylate (1.30g, 10.3mmol) in toluene (25 mL) were added potassium phosphate (2.18g, 10.25mmol), bis (dibenzylideneacetone) palladium (295mg, 0.512mmol) and 2-di-tert-butylphosphine-3, 4,5, 6-tetramethyl-2 ',4',6' -triisopropylbiphenyl (493mg, 1.02mmol), and after the addition, the resulting mixture was stirred at 115 ℃ overnight under nitrogen. Ethyl acetate (100 mL) was added, the mixture was filtered, and the filtrate was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =2, elution: 7) to give methyl 2- (3-cyano-1-cyclopropylmethyl-1H-indol-5-yl) -2H-1,2, 3-triazole-4-carboxylate (40) (211 mg). The yield thereof was found to be 19.2%.

Step C: a mixture containing compound 40 (50mg, 0.155mmol), lithium hydroxide hydrate (26.1mg, 0.622mmol), water (1 mL) and THF (4 mL) was stirred at room temperature overnight. Water (10 mL) was added and the pH adjusted to 1-2 with 1M hydrochloric acid. Extracted with ethyl acetate (20 mL. Times.3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by preparative HPLC to give 2- (3-cyano-1-cyclopropylmethyl-1H-indol-5-yl) -2H-1,2, 3-triazole-4-carboxylic acid (41). ¹ H NMR(DMSO-d ₆ ，400MHz)δ8.54(s，1H)，8.52(s，1H)，8.24(d，J＝2.0Hz，1H)，8.08-7.98(m，2H)，4.20(d，J＝7.2Hz，2H)，1.37-1.32(m，1H)，0.59-0.55(m，2H)，0.48-0.45(m，2H)。MS(ESI，m/z)：307.9[M+H] ⁺ 。

Example 10: synthesis of 2- [ 3-cyano-1 (-tetrahydrofuran-3-yl) -1H-indol-5-yl ] -2H-1,2, 3-triazole-4-carboxylic acid (44)

Experimental procedure for the synthesis of compound 44 see example 9 wherein cyclopropylmethyl bromide in step A of example 9 is replaced with 3-iodotetrahydrofuran. ¹ H NMR(DMSO-d ₆ ，400MHz)δ8.53(s，1H)，8.48(s，1H)，8.24(d，J＝2.0Hz，1H)，8.09-8.00(m，2H)，5.44-5.40(m，1H)，4.20-4.12(m，1H)，3.99-3.98(m，2H)，3.87-3.83(m，1H)，2.58-2.54(m，1H)，2.22-2.21(m，1H)。MS(ESI，m/z)：323.9[M+H] ⁺ 。

Example 11: synthesis of 2- (3-cyano-1-cyclobutyl-1H-indol-5-yl) -2H-1,2, 3-triazole-4-carboxylic acid (47)

Experimental procedure for the synthesis of compound 47 see example 9 wherein cyclopropylmethyl bromide in step a of example 9 is replaced with cyclobutane bromide. ¹ H NMR(DMSO-d ₆ ，400MHz)δ8.69(s，1H)，8.51(s，1H)，8.22(s，1H)，8.04(dd，J＝2.0，8.8Hz，1H)，7.91(d，J＝8.8Hz，1H)，5.15-5.11(m，1H)，2.55-2.52(m，2H)，2.49-2.48(m，2H)，1.91-1.86(m，2H)。MS(ESI，m/z)：308.0[M+H] ⁺ 。

Example 12: synthesis of 1- (3-cyano-1-cyclopropyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylic acid (50)

Step A: a mixture containing the compound 5-bromo-1H-indazole-3-carbonitrile (2.0g, 9.01mmol), cyclopropylboronic acid (1.55g, 18.0mmol), copper acetate (1.64g, 9.01mmol), potassium tert-butoxide (1.01g, 9.01mmol), DMAP (3.30g, 27.0mmol), and toluene (400 mL) was stirred under nitrogen at 95 ℃ overnight. After cooling to room temperature, ethyl acetate (400 mL) was added, and insoluble materials were removed by filtration through Celite. The filtrate was washed with saturated brine (100 mL. Times.2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, elution: 7) to give 5-bromo-1-cyclopropyl-1H-indazole-3-carbonitrile (48) (630 mg). The yield thereof was found to be 26.7%.

And B: a mixture containing ethyl 1H-pyrazole-4-carboxylate (53.5mg, 0.382mmmol) and compound 48 (100mg, 0.382mmol), potassium carbonate (105mg, 0.763mmol), cuprous iodide (72.7mg, 0.382mmol), N' -dimethylethylenediamine (33.6mg, 0.382mmol) and DMF (2 mL) was stirred at 110 ℃ for 3 hours under nitrogen. After cooling to room temperature, water (20 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.2), and the combined organic phases were washed with saturated brine (20 mL. Times.2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, elution: 4) to give ethyl 1- (3-cyano-1-cyclopropyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylate (49) (100 mg). The yield thereof was found to be 81.5%.

And C: a mixture containing compound 49 (100mg, 0.311mmol), lithium hydroxide hydrate (26.1mg, 0.622mmol), water (0.5 mL) and THF (2 mL) was stirred at room temperature overnight. Water (10 mL) was added, the pH was adjusted to 3-4 with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL. Times.3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by preparative HPLC to give 1- (3-cyano-1-cyclopropyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylic acid (50). 1H NMR (DMSO-d 6, 400 MHz) δ 12.68 (s, 1H), 9.23 (s, 1H), 8.45 (t, J =0.8hz, 1h), 8.26-8.23 (m, 1H), 8.11-8.09 (m, 2H), 4.10 (t, J =5.2hz, 1h), 1.24-1.22 (m, 4H). MS (ESI, m/z): 293.9[ M ] +H ].

Example 13: synthesis of 1- (7-fluoro-3-iodo-1-isopropyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylic acid (54)

Step A: a mixture containing ethyl 1H-pyrazole-4-carboxylate (1.30g, 9.30mmol) and 5-bromo-7-fluoro-1H-indazole (2.0g, 9.30mmol), potassium carbonate (2.57g, 18.6 mmol), cuprous iodide (1.77g, 9.30mmol), N' -dimethylethylenediamine (820mg, 9.30mmol) and DMF (40 mL) was stirred at 110 ℃ for 3 hours under nitrogen. After cooling to room temperature, water (120 mL) was added, extraction was performed with ethyl acetate (50 mL. Times.2), and the combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, 30-5 elution) to give ethyl 1- (7-fluoro-1H-indazol-5-yl) -1H-pyrazole-4-carboxylate (51) (2.10 g). The yield thereof was found to be 82.3%.

And B, step B: potassium carbonate (4.23g, 30.6 mmol) and iodine (3.89g, 15.3 mmol) were added to a solution of compound 51 (2.10 g, 7.66mmol) in DMF (40 mL) in an ice-water bath, and after the addition was complete, the resulting mixture was stirred at room temperature overnight. Water (120 mL) was added, extraction was performed with ethyl acetate (150 mL. Times.2), and the combined organic phases were washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1: 5-5. The yield thereof was found to be 32.6%.

And C: a mixture containing compound 52 (790mg, 1.97mmol), bromoisopropane (720mg, 5.85mmol), cesium carbonate (1.92g, 5.89mmol) and acetonitrile (14 mL) was stirred at 60 ℃ overnight. Cooled to room temperature and filtered to remove insoluble matter. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1: 20-1, elution) to give ethyl 1- (7-fluoro-3-iodo-1-isopropyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylate (53) (550 mg). The yield thereof was found to be 69.8%.

Step D: a mixture containing compound 53 (220mg, 0.497mmol), 2M sodium hydroxide solution (4 mL) and THF (1 mL) was stirred at 50 ℃ for 0.5 h. Water (15 mL) was added and extracted with dichloromethane (10 mL. Times.2) with the product in the aqueous phase. Adjusting the pH value of the water phase to 2-3 by using 2M hydrochloric acid, filtering, and recrystallizing a filter cake by using ethyl acetate/petroleum ether to obtain the 1- (7-fluoro-3-iodo-1-isopropyl-1H-indazol-5-yl) -1H-pyrazole-4-formic acid (54). ¹ H NMR(DMSO-d ₆ ，400MHz)δ9.21(s，1H)，8.13(s，1H)，8.09(d，J＝1.6Hz，0.5H)，8.06(d，J＝1.6Hz，0.5H)，7.84(d，J＝1.6Hz，1H)，5.11-5.05(m，1H)，1.54(d，J＝6.4Hz，6H)。MS(ESI，m/z)：414.9[M+H] ⁺ 。

Example 14: synthesis of 1- (3-cyano-7-fluoro-1-isopropyl-1H-indazol-5-yl) -1H-pyrazole-4-carboxylic acid (55)

The experimental procedure for the synthesis of compound 55 starting from compound 54 is described in example 4, step G. ¹ H NMR(DMSO-d ₆ ，400MHz)δ9.28(s，1H)，8.34(d，J＝1.6Hz，1H)，8.17-8.14(m，2H)，5.24-5.19(m，1H)，1.59(d，J＝6.4Hz，6H)。MS(ESI，m/z)：314.1[M+H] ⁺ 。

Example 15: synthesis of 2- (3-cyano-1-isopropyl-1H-indazol-5-yl) isonicotinic acid (57)

Step A: a mixture of compound 25 (500mg, 1.89mmol), pinacol diboron (721mg, 2.84mmol), potassium acetate (557mg, 5.68mmol) and 1,1' -bisdiphenylphosphinoferrocene palladium dichloride (139mg, 0.190mmol) and dioxane (10 mL) was stirred at 80 ℃ overnight. Cool to room temperature, filter, and rinse the filter cake with ethyl acetate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether =1, elution: 10) to give 1-isopropyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) 1H-indazole-3-carbonitrile (56) (360 mg). The yield thereof was found to be 61.2%.

And B: to a mixture containing compound 56 (200mg, 0.642mmol), 2-bromopyridine-4-carboxylic acid (130mg, 0.643mmol), potassium carbonate (178mg, 1.29mmol), dioxane (2.5 mL) and water (0.5 mL) was added [1,1' -bis (diphenylphosphino) ferrocenium]Palladium dichloride (52mg, 0.064mmol) was added and the resulting mixture was stirred under nitrogen at 85 ℃ for 2 hours. Cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (30 mL. Times.2) and the product was in the aqueous phase. Water (I)The phases were adjusted to pH 3-4 with 1M hydrochloric acid, then extracted with ethyl acetate (30 mL. Times.2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by preparative HPLC to give 2- (3-cyano-1-isopropyl-1H-indazol-5-yl) isonicotinic acid (57). ¹ H NMR(DMSO-d ₆ ，400MHz)δ8.88(d，J＝4.8Hz，1H)，8.65(s，1H)，8.50(s，1H)，8.40(dd，J＝1.6，9.2Hz，1H)，8.13(d，J＝8.8Hz，1H)，7.82(d，J＝8.8Hz，1H)，5.30-5.23(m，1H)，1.58(d，J＝6.8Hz，6H)。MS(ESI，m/z)：307.3[M+H] ⁺ 。

Example 16: xanthine oxidase activity inhibition assay

1. Principle of

The inhibition of Xanthine Oxidase activity was tested by a two-enzyme coupling reaction of Xanthine Oxidase (XO) and Horseradish Peroxidase (HRP) and their substrates. Xanthine oxidase first oxidizes hypoxanthine to produce xanthine and hydrogen peroxide, and further oxidizes xanthine to produce uric acid and hydrogen peroxide. Then, the hydrogen peroxide is catalyzed by horseradish peroxidase to react with 10-acetyl-3,7-dihydroxyphenoxazine (Ampliflu Red) to generate a strong fluorescent compound Resorufin (Resorufin), and the fluorescence intensity of the Resorufin is determined to be in direct proportion to the xanthine oxidase activity by a fluorescence enzyme reader.

2. Test reagents and apparatus

Febuxostat (Febuxostat) was purchased from beijing allied medicinal chemical technology limited; XO, ampliflu Red and hypoxanthine were purchased from Sigma-Aldrich Co., LLC; HRP was purchased from Shanghai-derived leaf Biotechnology, inc.; 96-well polypropylene reaction plates were purchased from Greiner Bio One; DMSO was obtained from national chemical group, chemicals, inc.

Vitor X4 plate reader is available from Perkin Elmer, inc.

3. Preparation of test Compound and reaction solution

Certain amounts of test compounds 15, 24, 28, 32, 35, 38, 41, 44, 47, 50, 57 and the control compound febuxostat were dissolved in DMSO (product of national drug group chemical agents limited). Test compounds were serially diluted 2.5-fold in 200-fold concentration solution in DMSO in 96-well polypropylene reaction plates. And further diluted in ultrapure water to give a 3-fold concentration of serially diluted solution.

Reaction solution a: a xanthine oxidase solution of 6mU/mL was prepared in a 0.1M Tris-HCl buffer (pH 7.5).

Reaction solution B: a mixture of 0.6U/mL horseradish peroxidase solution, 0.15mM Ampliflu Red and 0.3mM hypoxanthine was prepared in 0.1M Tris-HCl (pH 7.5) buffer solution. The solution is prepared at 4 ℃ in the dark.

4. Test methods and results

mu.L of reaction solution A was mixed with 9. Mu.L of a 3-fold concentration serial dilution of the test compound in a 96-well test plate, placed on a plate shaker, and mixed at 100rpm for 30 minutes at 30 ℃. Then, 9. Mu.L of the reaction solution B was added. The enzymatic reaction was carried out at 30 ℃ for 30 minutes. The fluorescence intensity at 530nm for excitation and 590nm for emission was measured with a microplate reader. The 50% Inhibitory Concentrations (IC) of the test compound and the control compound were calculated using the software Graph Pad Prism 5, with the fluorescence intensity of the no xanthine oxidase control at 0% and the fluorescence intensity of the no test compound control at 100% ₅₀ )。

The test results are shown in Table 1. As seen from the results in table 1, the compounds provided by the present invention exhibited excellent xanthine oxidase inhibitory effects in vitro pharmacological tests.

Xanthine oxidase inhibitor Activity IC of the Compounds of Table 1 ₅₀

Example 17: experimental study of Compounds on treatment of hyperuricemia in rats

1. Experimental Material

1. Test drug

Compounds 15, 24 and 38 were all white powders and compound 57 was a pale yellow powder, ground just before use using 0.5% CMC-Na to make suspensions of the corresponding concentrations (0.2 and 0.4 mg/mL) for gavage.

Febuxostat, purchased from Sigma, was milled using 0.5% cmc-Na immediately prior to use to prepare suspensions of the corresponding concentrations (0.2 and 0.4 mg/mL) for gavage.

2. Animals and breeding

2.1 animal species and sources

SD rats, SPF grade, male, weight 180-220g, purchased from shanghai slek laboratory animals llc, production license number: SCXK (Shanghai) 2017-0005, quality certification number: 20170005050604.

2.2 feeding conditions

The rats are all raised in an independent air supply cage, the air cleanliness is 10000 levels, and the laboratory temperature is 26 +/-2 ℃; relative humidity is 60% -80%; number of air exchanges per hour: 10-15 times per hour; the illumination period is as follows: 12 Day/12 night, 3 per cage.

Feed: the rat complete granulated feed is purchased from cooperative medical bioengineering, LLC of Jiangsu province, and the quality of the rat complete granulated feed meets GB14924.1-2001 'Universal quality Standard for Compound feed for laboratory animals'.

Padding: the sterilization particle padding is purchased from cooperative medical bioengineering, limited liability company of Jiangsu province.

Drinking water: the drinking purified water can be freely drunk after acidification.

3. Main instrument equipment

Varioskan LUX multi-functional microplate reader is available from Thermo, usa; BS210S precision electronic balance (0.1 mg-10 g) purchased from Sidoris, germany; FEJ-200 electronic balance (0.1-200 g) was purchased from Bao electronics, inc., of Fuzhou Furiheng; pacific TII + Genpure XCAD PLUS UV/TOC/UF pure water ultra pure water system was purchased from Thermo, USA.

4. Primary reagent

Uric acid detection kit (phosphotungstic acid reduction method), batch number: 20210515, purchased from Nanjing, to build the institute of bioengineering; potassium Oxazinate, cat No. O0164, batch No. T6GKM-TA, available from Tokyo chemical industries, inc. (TCI), japan; sodium carboxymethylcellulose (CMC-Na), lot No. 20170810, chemically pure, purchased from chemicals group chemicals ltd.

2. Experimental methods

1. Grouping

SD rats 72, male, after one week of acclimation, had a body weight of about 200-230g. The weight of the animal is divided into 10 groups at random, and each group comprises 6 animals: (1) CMC-Na% in the normal group (0.5), (2) CMC-Na% in the model group (0.5), (3) febuxostat 1mg/kg, (4) febuxostat 2mg/kg, (5) Compound 15,1mg/kg, (6) Compound 15,2mg/kg, (7) Compound 24,1mg/kg, (8) Compound 24,2mg/kg, (9) Compound 38,1mg/kg, (10) Compound 38,2mg/kg, (11) Compound 57,1mg/kg, (12) Compound 57,2mg/kg. Each group of medicines is prepared into corresponding concentration suspension, and the administration volume is 0.5mL/100g.

2. Model establishment, dosing regimen and detection index

After purchasing adaptive feeding, the rats of each group are fasted for 12h, respectively molded by potassium oxonate according to 300mg/kg dose ip, and each tested drug group is respectively administered for 1 time by intragastric administration 0.5h after molding. Collecting blood through retroorbital venous plexus before injection of Potassium Oxonate and 1,3 and 5h after injection of Potassium Oxonate, centrifuging at 3500rpm for 10min, and measuring uric acid level at each time point by taking 30 μ L of serum.

Then, the rats are molded with potassium oxonate ip at a dose of 300mg/kg every day for 2 consecutive days, and the tested drug groups are respectively administered by intragastric administration for 1 time after molding. On day 3 of administration, fasted rats of 12h were collected before injection of Potassium Oxonate and after injection of Potassium Oxonate 1,3, 5h, respectively, by retroorbital venous plexus blood sampling, as in the test method on day 1, centrifuged at 3500rpm for 10min, and 30. Mu.L of serum was taken to determine uric acid levels at each time point.

3. Data processing and statistical method

The measurement data of each test are expressed as (mean) ± s (standard deviation), and the significance of the comparison among the groups is examined by ANOVA-Dunnett T test, wherein P <0.05 is taken as a significance index, and P <0.01 is taken as a very significance index.

3. Results of the experiment

1. Effect of 1 day administration on serum uric acid levels in rats

Compared with the normal group, the serum uric acid level of the model group is obviously increased after 1,3 and 5 hours of model building (P < 0.01). Compared with a time point model group, the 1mg/kg group and the 2mg/kg group of febuxostat can obviously reduce the serum uric acid levels (P < 0.01) for 1,3 and 5h after the model is made. Compared with the model group, the 2mg/kg group of the compound 15 can obviously reduce the serum uric acid level 1h after the model building (P < 0.01), the 1 and 2mg/kg groups of the compound 24 can obviously reduce the serum uric acid level 1h after the model building (P < 0.01), the 1 and 2mg/kg groups of the compound 38 can obviously reduce the serum uric acid level 1,3 and 5h after the model building (P < 0.01), and the 1 and 2mg/kg groups of the compound 57 can obviously reduce the serum uric acid level 1,3 and 5h after the model building (P <0.01 or P < 0.05). The results are shown in Table 2.

TABLE 2 Effect of 1 day dosing on Potassium Oxonate-induced serum uric acid levels in hyperuricemic rats

Note: ^## P<0.01, compared to a simultaneous point solvent set; * P<0.01, compared to a simultaneous point model set.

2. Effect of 3 days of administration on rat serum uric acid levels

Compared with the normal group, the potassium oxonate model group has the advantage that the serum uric acid water level is obviously increased (P is less than 0.01) after 1 hour and 3 hours of molding. Compared with the model group at the same time point, the 1mg/kg group and the 2mg/kg group of febuxostat can obviously reduce the serum uric acid level (P <0.05 or P < 0.01) at1, 3 and 5h after the model building. Compared with the model group, the 2mg/kg group of the compound 24 can obviously reduce the serum uric acid level (P < 0.01) after the model is built for 3 hours, the 1 and 2mg/kg groups of the compound 38 can obviously reduce the serum uric acid level (P < 0.01) after the model is built for 1,3 and 5 hours, and the 1 and 2mg/kg groups of the compound 57 can obviously reduce the serum uric acid level (P < 0.01) after the model is built for 1 and 3 hours. The results are shown in Table 3.

TABLE 3 Effect of 3 days of administration on Potassium Oxonate-induced serum uric acid levels in hyperuricemic rats

Claims

1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

y is N or C-R ⁶ ；

R ¹ Is cyano, nitro or halogen;

R ⁶ is hydrogen, deuterium, halogen, cyano, C _1-6 Alkyl, substituted C _1-6 Alkyl radical、C _1-6 Alkoxy, substituted C _1-6 Alkoxy radical, C _3-6 Cycloalkyl or substituted C _3-6 A cycloalkyl group; wherein R is ⁶ The substituent in each group is selected from deuterium, cyano, nitro, halogen and C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Alkylthio or C _3-6 One or more of cycloalkyl;

ar is the following unsubstituted or substituted group: 1,2, 3-triazolyl, pyrazolyl, pyridyl or thienyl, wherein the substituents in each group to which Ar relates are selected from deuterium, halogen or C _1-3 One or more of alkyl; and when Y is C-R ⁶ When Ar is only an unsubstituted or substituted 1,2, 3-triazolyl group;

R ⁷ is carboxyl or C _2-6 An ester group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar is a substituted or unsubstituted group of:

wherein the substituents in each group related to Ar are selected from deuterium, halogen or C _1-3 One or more of alkyl groups.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ² 、R ³ Or R ⁴ Each independently hydrogen, deuterium, cyano or halogen.

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is C _3-6 Alkyl, substituted C _1-6 Alkyl radical, C _3-6 Cycloalkyl, substituted C _3-6 Cycloalkyl, C _3-6 Heterocycloalkyl or substituted C _3-6 A heterocycloalkyl group; wherein R is ⁵ The substituent in each group is selected from deuterium, cyano, nitro, halogen and C _1-5 Alkyl radical, C _1-5 Alkoxy or C _3-6 One or more cycloalkyl groups.

5. A compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Is C _3-6 Alkyl, substituted C _1-6 Alkyl radical, C _3-6 Cycloalkyl, substituted C _3-6 Cycloalkyl, tetrahydrofuran, substituted tetrahydrofuran, tetrahydrothiophene, substituted tetrahydrothiophene, tetrahydropyrrole, or substituted tetrahydropyrrole; wherein R is ⁵ The substituent in each group is selected from deuterium, cyano, nitro, halogen and C _1-5 Alkyl radical, C _1-5 Alkoxy or C _3-6 One or more cycloalkyl groups.

6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁶ Is hydrogen, deuterium, halogen, cyano or C _1-5 An alkyl group.

7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ⁷ Is a carboxyl group.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

9. a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, together with pharmaceutically acceptable excipients.

10. The use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of xanthine oxidase inhibitors, in particular for the manufacture of anti-gout drugs or anti-hyperuricemia drugs.